Summary: In the mid-1980s we carried out a prospective study of early pregnancy in which we enrolled 221 health women who were planning to become pregnant. These women collected daily urine specimens for up to six months. We've assayed these specimens to describe the hormonal events of the menstrual cycle and early pregnancy. 155 women became clinically pregnant during the study, while 44 had pregnancies that ended so early that the pregnancies were detectable only by assay of urinary human chorionic gonadotropin. This unique study has been called a landmark, and continues to provide a rich resource for the description of the earliest stages of pregnancy. (More than 30,000 urine samples are still being stored.) We've published more than 40 papers from this study over the past two decades, some of which have led to new understanding of the fundamental processes of conception and early pregnancy. [unreadable] In addition, we have continued to make use of large population registries in order to pursue basic questions on pregnancy and maternal and infant health. We have worked especially closely with Norwegian colleagues in the analysis of the Norwegian Medical Birth Registry. [unreadable] [unreadable] Last year's progress.[unreadable] It is well known that clinical miscarriages can be accompanied by heavy bleeding. However, there has been no description of the vaginal bleeding that accompanies loss of pregnancy earlier in gestation. Such bleeding is typically mistaken for ordinary menstrual bleeding, since women usually do not realize they are pregnant. We used menstrual diary data from 42 women with early losses to assess the amount of bleeding with early losses, compared with the women's normal (non-conception) menstrual cycles. On average there was no increased bleeding with early loss. Unexpectedly, the earliest losses were accompanied by less bleeding than average, while later (but still subclinical) losses had slightly heavier bleeding. Reasons for bleeding less than the usual menstrual cycle with the earliest losses are unknown. We speculate that this may reflect suboptimal priming of the endometrial lining that contributes to the loss itself.[unreadable] We have pursued our interest in preeclampsia using data from the Norwegian Medical Birth Registry. Preeclampsia remains one of the most enigmatic of all diseases, manifest only in pregnancy and "cured" by delivery of the fetus. While a familial risk has been recognized, it has not been clear how much of the risk is from genes carried by the mother, or genes carried by the fetus. We demonstrated that both play a distinct role. This may provide direction for further studies that focus on candidate genes for preeclampsia.[unreadable] In another study of preeclampsia, we showed that induction of delivery (done to protect mothers with preeclampsia from developing more severe disease) has apparently benefited the fetus as well as the mother, at least in terms of the fetus' survival. We used data from Norway to show that fetal mortality associated with preeclampsia has dropped dramatically over recent decades, as doctors increasingly intervened to deliver the pregnancy prematurely. Such preterm delivery might be expected to put the newborn at some increased jeopardy, but we saw no evidence of higher mortality during the neonatal period with preeclampsia. This does not rule out the possibility of later problems from preterm delivery, but it does provide some preliminary reassurance that current medical practices to protect mothers with preeclampsia are not producing a compensatory cost in the newborn. [unreadable] Public Health or Environmental Health Significance: Successful reproduction is highly valued by most couples (as evidenced by the thousands who resort to advanced technologies in order to conceive). For society as a whole, there are many costs of reproductive failure, including the long-term care required by individuals born with disabilities. The underlying goal of our research program to understand the causes of reproductive problems, in order to avert problems that are preventable. [unreadable] Research Accomplishments: Mothers lose about 25% of their pregnancies before the women even know they are pregnant. We have showed that the bleeding with such pregnancy losses is, on average, indistinguishable from the bleeding of ordinary menses. We also showed that the medical practice of preventing the advance of maternal preeclampsia by delivering women before the baby has reached term has actually benefited the fetus as well. Fetal mortality associated with preeclampsia has declined over recent decades as intervention has become more common. We found no evidence that the babies being delivered early suffered increased mortality during the neonatal period. [unreadable]